1. Field of the Invention
The present invention relates to pharmaceutical drug delivery vehicles. In particular, this invention relates to drug delivery vehicles which can be administrable as a drop, and which reversibly increase in loss modulus, storage modulus, or both, upon contact with the eye, skin, mucous membrane or a body cavity.
2. Description of Related Art
A variety of gelling drug delivery systems have been developed in an effort to prolong the contact or residence time of pharmaceutical drugs at target sites on or within the body. Drug delivery vehicles containing polysaccharide polymers which gel in response to a pH change have been proposed, such as those described in U.S. Pat. Nos. 4,136,173, 4,136,177, and 4,136,178, for example. However, compositions having an initial pH which is too low are irritating when administered to sensitive parts of the body, such as the eye.
Alternatively, drug delivery systems which gel in response to changes in ionic strength have been proposed, such as those described in European Patent No. 0 227 494 B1 and U.S. Pat. No. 4,861,760. The rates of gelation for systems which gel in response to ionic changes are dependant on the supply and diffusion of ions, and consequently are generally slower than those for thermally gelling systems because the diffusion of ions is generally a slower process than heat transfer. In addition, certain charged drug compounds cannot be used in drug delivery systems which gel in response to changes in ionic strength because they may cause premature gelation.
U.S. Pat. No. 5,212,162 discloses compositions containing both a gelling polysaccharide and a drug carrier substrate, such as finely-divided solids, colloidal particles, or soluble polymers and/or polyelectrolytes which are capable of selective adsorption or binding with drug molecules. The polysaccharide is capable of reversibly gelling based on a change in ionic strength or pH. Such factors as a change in temperature, amount and type of drug carrier substrate, and characteristics and concentrations of drugs or other adjuvants may also affect the ability of the polysaccharide to undergo a liquid-to-gel transition. The preferred polysaccharides are carrageenans.
Drug delivery systems which gel in response to temperature changes have also been proposed. For example, drug delivery systems utilizing Tetronic.RTM., Pluronic.RTM., or other polyols have been disclosed in U.S. Pat. Nos. 4,474,751; 4,474,752; and 4,188,373. U.S. Pat. Nos. 5,124,151; and 5,306,501 also disclose thermally gelling systems. Several disadvantages are associated with these materials. One disadvantage common to all of these thermally gelling systems is that they require a large amount of polymer (10-50 wt. %), and such large amounts of polymer can be irritating and/or toxic to the eye. Another disadvantage of some of the known thermally gelling systems is that they gel irreversibly. Such thermally irreversible gels require special precautions for product shipping and handling.
It is an inherent requirement that drug delivery systems which gel solely in response to temperature changes undergo the "sol-gel" transition at temperatures lower than physiologic temperature. It is known that methylcellulose and its hydroxyalkyl derivatives reversibly gel with increases in temperature. Generally, however, the liquid-to-gel transition temperature for cellulose polysaccharides, such as methylcellulose, occurs at temperatures well above physiologic temperature. See, for example, N. Sarkar, "Thermal Gelation Properties of Methyl and Hydroxypropyl Methylcellulose," J. of Applied Polymer Science, Vol. 24, 1073-1087 (1979).
It is known that the addition of salts to methylcellulose can adjust its liquid-to-gel transition temperature; however, the amount of salt required to adjust the transition temperature to the physiologic temperature range often results in hyperosmotic compositions which are irritating. It is also known that the gelation temperature of methylcellulose may be altered by adding hydroxypropyl substituents, but the reported change does not bring the gelation temperature any closer to physiologic temperatures. N. Sarkar, J. of Applied Polymer Science, Vol. 24, 1084 (1979).
One effort to utilize cellulose polysaccharides in liquid pharmaceutical drug delivery vehicles is disclosed in PCT Application Publication No. WO 92/09307. This reference discloses gelable carder compositions containing a water-soluble, nonionic cellulose ether, such as ethylhydroxyethylcellulose, and a charged surfactant. The reference gels are formed by strong hydrophobic interaction between the polymer and the charged surfactant. However, charged surfactants may be toxic if delivered to sensitive parts of the body, such as the eye. Additionally, other adjuvants may detrimentally influence the polymer-charged surfactant gelation.
Various drug delivery systems employing combinations of two types of gelling polymers have also been disclosed. U.S. Pat. No. 5,077,033 discloses a thermally irreversible gel system comprising a combination of polyoxyalkylene and ionic polysaccharides. U.S. Pat. No. 5,296,228 discloses aqueous reversibly gelling polymeric solutions containing ion exchange resin particles. The polymeric component of the solution may be a pH sensitive polymer, a temperature sensitive polymer, or combinations of both pH-sensitive polymers and temperature sensitive polymers. U.S. Pat. No. 5,252,318 also discloses reversibly gelling aqueous compositions containing combinations of polymers, in this case at least one pH-sensitive reversibly gelling polymer and at least one temperature sensitive reversibly gelling polymer. One disadvantage common to systems which require pH changes in order to gel is that they must be administered at a relatively low pH, typically in the range of 2.5-4.5. Systems administered to the eye at such a relatively low pH are irritating.